(a) Field
The subject matter disclosed generally relates to novel chemical compounds and methods. More particularly, the invention provides novel derivatives of podophyllotoxin with a gem-difluoronated compound, having improved conformational and chemical stability, and having improved cytotoxicity, and methods of synthesizing and using such compounds. Preferred compounds are useful for the treatment of abnormal cell growth, such as cancers.
(b) Related Prior Art
Podophyllotoxin 1 is a lignan isolated from the roots of two plants Podophyllum peltatum (North America) and Podophyllum emodi (Asia). It has strong antimitotic activity by inhibiting polymerization of tubulin. Too toxic to be used in chemotherapy, it has given rise to many antitumoral compounds after structural modifications. Among them, glycosylated derivatives, compounds which are usually less toxic and more water-soluble, have emerged. For example, etoposide 2 is used in the treatment of small-cell lung cancer, bladder and testicular cancer, lymphomas, acute leukemias, and Kaposi sarcomas.

Nitrogen-containing derivatives of podophyllotoxin such as GL-331 5, NPF 6 or TOP-53 7 also show very interesting activities.

These molecules derived from the demethylepipodophyllotoxin structure, such as compound 2, 3 and 4, are inhibitors of topoisomerase II, an enzyme which catalyzes nicking and then reformation of the two DNA strands.
Nitrogen-containing compounds of podophyllotoxin, with an amine function substituted with a gem-difluorinated glycoside have been reported in U.S. Pat. No. 8,236,935. These compounds, 8 and 9, have significant cytotoxicity and the presence of a glycoside moiety improves the solubility of these compounds in aqueous medium and the gem-difluoromethylene group not only mimics the oxygen atom, but also prevents the hydrolysis of the glycoside moiety from the core structure, thus improving the pharmacological activity of these molecules. However, this class of molecules exists as an anomeric mixture with unstable conformations which may suffer from degradation driven by ring-opening process, thus resulting in loss of biological activities, and potentially poor pharmacokinetics properties.

Therefore, there is a need for derivatives of podophyllotoxin with a gem-difluoronated compound having improved conformational stability.
Furthermore, there is a need for derivatives of podophyllotoxin with a gem-difluoronated compound having improved chemical stability.
Furthermore, there is a need for derivatives of podophyllotoxin with a gem-difluoronated compound having improved cytotoxicity against cancer cells.
Also, there is a need for novel synthetic methods and processes to synthesize derivatives of podophyllotoxin with a gem-difluoronated compound.